Package leaflet: Information for the patient

NITROUS OXIDE SAPIO LIFE medicinal gas liquefied

Nitrous oxide
Generic medicine
Please read all of this leaflet carefully before you use this medicine because it contains important information for you.

Keep this leaflet. You may need to read it again.
If you have any questions, ask your doctor, pharmacist or nurse.
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

Contents of this leaflet:

What AZOTO PROTOSSIDO SAPIO LIFE is and what it is used for
What you need to know before using AZOTO PROTOSSIDO SAPIO LIFE
How to use AZOTO PROTOSSIDO SAPIO LIFE
Possible side effects
How to store AZOTO PROTOSSIDO SAPIO LIFE
Contents of the pack and other information

1. What AZOTO PROTOSSIDO SAPIO LIFE is and what it is used for

AZOTO PROTOSSIDO SAPIO LIFE contains nitrous oxide, a medicinal gas indicated for:

inducing anaesthesia (loss of sensation, consciousness, and pain, associated with muscle relaxation) during surgical procedures, in combination with other anaesthetics administered by inhalation (inhalational route) or by intravenous injection (intravenous route).
providing rapid-onset, temporary pain relief (analgesia) and inducing sedation during short surgical procedures, trauma, burns, dental procedures (on teeth and gums), otorhinolaryngological procedures (on nose, ears, and throat), and during childbirth.

2. What you need to know before using NITROUS OXIDE SAPIO LIFE

Do not use NITROUS OXIDE SAPIO LIFE if:

you are allergic to nitrous oxide;
you suffer from intestinal distension and/or altered intestinal transit (intestinal obstruction);
you are due to undergo surgery involving a risk of gas bubble formation in the blood (gas embolism);
you are due to undergo surgery on the middle ear;
you suffer from lung diseases (emphysema, pneumothorax, and gas embolism);
you are in the first or second trimester of pregnancy (see section “Pregnancy and breastfeeding”);
pure oxygen needs to be administered to you or you have difficulty breathing;
you have dived within the last 48 hours;
you are due to undergo surgery requiring the use of cardiopulmonary bypass, a machine used to maintain blood circulation;
you have a perforated intestine;
you have recently received a gas injection into the eye;
you have intestinal obstruction, ear inflammation (otitis), ear blockage, or sinusitis (infection of the nose and paranasal sinuses);
there is suspicion or confirmation that you have increased intracranial pressure;
you have shown a decreased level of consciousness and cooperation during treatment with nitrous oxide for analgesia;
you have suffered head trauma (closed head injury) or have severe head diseases;
you are at risk of developing vitamin B and/or folate deficiency and anemia (reduction in hemoglobin, the protein that carries oxygen in the blood);
you have vitamin B deficiency for which treatment has not yet been established;
you have Biermer's anemia, a type of anemia;
you have Crohn’s disease (an intestinal disease);
you have diseases that may affect myelin sheaths (nerve coverings);
you have methionine deficiency (an amino acid);
you have been administered nitrous oxide for longer than 24 hours.

Warnings and precautions
Talk to your doctor, pharmacist, or nurse before using NITROUS OXIDE SAPIO LIFE if:

you abuse or have abused drugs/medicines, as there is an increased risk of developing dependence on nitrous oxide if used repeatedly. Your doctor will decide whether treatment with NITROUS OXIDE SAPIO LIFE is appropriate in your case.

Repeated or long-term use of nitrous oxide may increase the risk of vitamin B12 deficiency, which can lead to damage to the bone marrow or nervous system. Your doctor may perform blood tests before and after treatment to assess the consequences of any potential vitamin B12 deficiency.
Your doctor will administer nitrous oxide with caution in the following situations:

thoracic surgery, due to the risk of lung collapse (pneumothorax), expansion of emphysematous bullae, and risk of eliminating hypoxic vasoconstriction;
presence of uneliminated fluid accumulation in the airways;
endoscopic procedures using carbon dioxide as the insufflation gas;
neurosurgery, because nitrous oxide reduces the protective effect provided by barbiturates, increases cerebral blood flow, and raises pressure in any air-filled cavity or bubble within the skull;
low levels of hemoglobin (the oxygen-carrying protein) in the blood due to a specific type of anemia called sickle cell anemia;
after intraocular injection into the eye: a sufficient period of time must elapse, as there is a risk of visual disturbances;
prolonged anesthesia (lasting more than 6 hours);
high risk of nausea and vomiting;
in patients treated with bleomycin;
vegetarian patients;
if you are in the third trimester of pregnancy (see section “Pregnancy and breastfeeding”).

Other medicines and NITROUS OXIDE SAPIO LIFE
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines.
In particular, inform your doctor or pharmacist if you are taking:

opioids (opioid medicines used for pain);
benzodiazepines (medicines used to treat anxiety and insomnia);
barbiturates;
anesthetics (medicines used to induce anesthesia or reduce pain);
warfarin, a medicine that slows blood clotting;
methotrexate, a medicine used for immune disorders or tumors;
sodium nitroprusside, a medicine used to significantly lower blood pressure;
succinylcholine and other muscle relaxants (medicines that relax muscles).

Pregnancy and breastfeeding
If you are pregnant, suspect you may be pregnant, planning a pregnancy, or breastfeeding, consult your doctor or pharmacist before taking this medicine.
Pregnancy
The use of NITROUS OXIDE SAPIO LIFE is contraindicated during the first and second trimesters of pregnancy (see Do not use NITROUS OXIDE SAPIO LIFE if).
NITROUS OXIDE SAPIO LIFE may be used during the third trimester of pregnancy only if the doctor considers it strictly necessary. NITROUS OXIDE SAPIO LIFE may be used during labor.
The use of nitrous oxide should be avoided in cases of fetal distress. If NITROUS OXIDE SAPIO LIFE is used close to delivery, the newborn will be monitored for signs of possible respiratory difficulty.
Breastfeeding
It is not necessary to interrupt breastfeeding if you have been administered NITROUS OXIDE SAPIO LIFE for a short period of time.
Driving and using machines
Nitrous oxide affects your ability to drive or operate machinery. Avoid driving, operating machinery, and performing other activities requiring full attention for 24 hours after anesthesia with NITROUS OXIDE SAPIO LIFE.
After a short-term administration of NITROUS OXIDE SAPIO LIFE for pain relief, your doctor will monitor you to ensure all effects have worn off and that you are sufficiently alert to drive or operate machinery.

3. How to use NITROUS OXIDE SAPIO LIFE

Use this medicine exactly as instructed by your doctor or pharmacist. If you have any doubts, consult your doctor or pharmacist.
The doctor will decide whether this medicine can be administered, the dose to be given, and the duration of treatment, taking into account your health status and the concomitant administration of other anesthetic medicines to induce general anesthesia.
Your doctor will administer NITROUS OXIDE SAPIO LIFE to you in combination with oxygen through a tube inserted into your mouth or nose in the operating room, or via a close-fitting face or nasal mask in other settings. You will be able to breathe spontaneously or with the assistance of a respirator (assisted or mechanical ventilation).
Medical staff will monitor you throughout the administration and until you have fully regained consciousness.

If you use more NITROUS OXIDE SAPIO LIFE than you should
In case of overdose or prolonged exposure to NITROUS OXIDE SAPIO LIFE, the following may occur:

headache,
dizziness,
confusion,
weakness,
incoordination of movements,
vertigo,
memory disturbance (amnesia),
loss of language comprehension or expression abilities (aphasia),
sudden and temporary loss of consciousness (syncope),
disturbance of normal heart rhythm (arrhythmia),
unconsciousness,
death due to suffocation (asphyxia).

Treatment
The doctor will stop the administration, ensure airways remain open, provide assisted oxygenation, and initiate symptomatic treatment.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone experiences them.
If you experience any of the following reactions, your doctor will IMMEDIATELY STOP treatment and initiate appropriate therapy:

bluish discoloration of the skin and mucous membranes (cyanosis)

The following are the side effects of AZOTO PROTOSSIDO SAPIO LIFE:
Common (may affect up to 1 in 10 people):

nausea, vomiting
dizziness
headache
migraine

Uncommon (may affect up to 1 in 100 people):

swelling, increased volume of gas in the intestine
heightened sense of well-being (euphoria)
sensation of pressure in the ear, ear damage, rupture of the tympanic membrane (a membrane in the ear)
severe megaloblastic anaemia (anaemia due to vitamin B deficiency)
granulopenia/agranulocytosis (reduction in the number of a type of white blood cells)
leucopenia (reduction in the number of white blood cells)

Rare (may affect up to 1 in 1,000 people):

myelopathies (diseases of the bone marrow)

Very rare (may affect up to 1 in 10,000 people):

movement disorders, paraplegia (paralysis of the lower limbs), paraparesis (partial paralysis of the upper or lower limbs), epilepsy (sudden loss of consciousness with convulsive muscle movements), increased intracranial pressure (in the head), peripheral nervous system disease (peripheral neuropathy), brain disease (encephalopathy)
sensory disturbances, altered reflexes, decreased level of consciousness, hallucinations (seeing or perceiving things that do not exist), psychosis (mental disturbances), confusion, anxiety
ocular hypertension (increased pressure inside the eye), eye pain
retinal artery occlusion (blockage of a blood vessel in the eye)
blindness (loss of vision)
changes in heart rhythm (arrhythmias)
cardiac failure (inability of the heart to supply adequate blood flow to meet the body's needs)
hepatic necrosis (death of liver cells)
cerebral hyperperfusion syndrome (neurological disorders due to reduced blood flow to the brain)
increased pressure in inflated balloons
vitamin B deficiency
hyperhomocysteinaemia (increased levels of homocysteine in the blood)
muscle weakness
malignant hyperthermia (excessive oxygen consumption by muscles with increased body temperature)
multiple congenital anomalies (birth defects)
infertility
hypoxia (lack of oxygen in the body)
pneumothorax (accumulation of air in the pleural cavity, a space between the lungs and the pleura, a membrane surrounding the lungs)
hypotension (decrease in blood pressure)
shock (imbalance between oxygen availability and the body's demand)

Not known (frequency cannot be estimated from the available data):

dependence
effects on nerve function, sensations of numbness and weakness, usually in the legs
generalized epileptic seizures

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor, pharmacist or nurse. You may also report side effects directly via the website https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse.
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store NITROUS OXIDE SAPIO LIFE

Store at a temperature not exceeding 50°C.
Keep this medicinal product out of the sight and reach of children.
Do not use this medicinal product after the expiry date which is stated on the label after EXP. The expiry date refers to the last day of that month.
Do not dispose of any medicinal product via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. This will help protect the environment.

6. Package Contents and Other Information

What AZOTO PROTOSSIDO SAPIO LIFE Contains
The active substance is nitrous oxide 100%.
Description of the Appearance of AZOTO PROTOSSIDO SAPIO LIFE and Contents of the Package
AZOTO PROTOSSIDO SAPIO LIFE is a colourless gas with a slightly sweet odour, supplied in cylinders and cylinder packs (blue shoulder marked with "N O" or "nitrous oxide", and white cylinder) with a shut-off valve, as well as in fixed cryogenic containers.
Marketing Authorisation Holder
SAPIO LIFE S.r.l. – Via Silvio Pellico, 48 – 20900 Monza (MB)
Manufacturer
Cylinders and cylinder packs
Sapio Produzione Idrogeno Ossigeno S.r.L. – Via S. Simonetta, 27 – Caponago (MB)
Alfa Ossigeno S.r.l. - Via delle Industrie, 9 - Fisciano (Sa)
Fixed cryogenic containers
Alfa Ossigeno S.r.l. - Via delle Industrie, 9 - Fisciano (Sa)
Eurogas S.r.l. - Via Pradazzo, 22 - 26012 Castelleone (CR)

The following information is intended exclusively for physicians or healthcare professionals:
Precautions for Use
Repeated administration or exposure to nitrous oxide may lead to dependence.
Healthcare workers with occupational exposure to nitrous oxide should be carefully monitored.
The fraction of inspired oxygen (FiO₂) in the inhaled mixture must be at least 21% v/v during the induction phase. In practice, a lower limit of 30% v/v is often used. Oxygen tension must remain above physiological levels (100 mmHg), with haemoglobin oxygen saturation exceeding 97%, and in any case always above 60 mmHg, with haemoglobin oxygen saturation greater than 90%. Regular monitoring is required, either by measuring arterial oxygen tension (PaO₂) or by pulse oximetry (arterial oxygen saturation SpO₂), along with clinical assessment. The minimum effective oxygen concentration in the inhaled air should be established for each individual patient.
Nitrous oxide concentrations exceeding 50% v/v may impair protective reflexes and levels of consciousness. Concentrations above 60–67% v/v often cause unconsciousness and increase the risk of impaired protective reflexes.
If unexpected cyanosis occurs during anaesthesia or during induction, it is recommended to stop the administration of nitrous oxide and increase the inhaled oxygen fraction to 100%. If cyanosis does not resolve rapidly, or if the episode recurs during anaesthesia, possible causes to consider include equipment malfunction (delivery of a hypoxic mixture) or accidental interchange of medical gas lines connected to the anaesthetic machine. It is therefore advisable to attempt ventilation using a self-inflating bag filled with ambient air.
Following general anaesthesia involving high concentrations of nitrous oxide, the gas may diffuse from the blood into the alveoli, diluting alveolar oxygen. This may result in hypoxia (diffusion hypoxia), caused not only by the alveolar gas mixture but also by the reflex response to hypoxia, hypercapnia, and hypoventilation. To prevent this, 100% oxygen should be administered at the end of nitrous oxide administration instead of room air.
Monitoring of oxygen tension and oxygen saturation should continue for 15 minutes after the end of nitrous oxide administration.
Administration of nitrous oxide may increase pressure in the endotracheal tube cuff, potentially causing tracheal damage, or in any other inflated balloon used in procedures (e.g. vascular occlusion balloons). Additionally, when using nitrous oxide with a Swan-Ganz catheter, the generated pressure may displace the catheter into an occluded position, thereby altering pressure readings.
Medical devices containing air may malfunction (e.g. rupture) when exposed to nitrous oxide.
Nitrous oxide should not be used during laser surgery of the airways due to the risk of explosive combustion.
Nitrous oxide may increase pressure in the middle ear.
Administration of nitrous oxide should be performed with caution in the following situations:

Thoracic surgery, due to the risk of pneumothorax, expansion of emphysematous bullae, and the potential reversal of hypoxic vasoconstriction.
Presence of undrained airway collections.
Endoscopic procedures using carbon dioxide as the insufflation gas.
Neurosurgery, because nitrous oxide reduces the protective effect provided by barbiturates, increases cerebral blood flow, and raises pressure within any intracranial air pockets or bubbles.
Sickle cell anaemia.
After intraocular injection: a sufficient time interval must elapse due to the risk of visual disturbances.
Prolonged anaesthesia (>6 hours).
High risk of nausea and vomiting.
In patients treated with bleomycin, because increased oxygen concentration during inhalational sedation techniques raises the risk of pulmonary toxicity.
Vegetarian patients.

For Healthcare Personnel
Nitrous oxide is a colourless gas with a faintly sweet odour; it is non-toxic and non-flammable, but supports combustion. It is heavier than air and tends to accumulate in low-lying areas of the workplace.
Nitrous oxide exhaled by the patient gradually disperses into the ambient air of the room where it is used. The use of so-called "double masks" (active nasal masks), adequate ventilation rates in operating rooms (20 air changes per hour), and active scavenging systems from anaesthetic equipment should ensure that the average concentration remains below the maximum allowable concentration established by current regulations.
Furthermore, compliance with regulations regarding the use of nitrous oxide-containing products is required. As a general rule, healthcare personnel should avoid prolonged direct inhalation of exhaled air from patients.
Chronic exposure to low concentrations of nitrous oxide has been identified as a potential health risk. At present, it is not possible to determine whether a causal relationship exists between chronic exposure to low concentrations of nitrous oxide and specific diseases, but a potential link between chronic exposure and the development of tumours or other chronic diseases, reduced fertility, spontaneous abortion, and fetal malformations cannot be ruled out.
Dosage, Method and Duration of Administration
As an anaesthetic
Nitrous oxide, used exclusively in operating rooms or delivery rooms, must be administered in a mixture with oxygen at concentrations below 79%, using appropriate equipment that includes oxygen concentration monitoring and a safety system preventing the delivery of a hypoxic mixture (oxygen fraction (FiO₂) <21% v/v).
Nitrous oxide must not be administered at concentrations exceeding 79% v/v to ensure adequate FiO₂. In patients with reduced oxygen saturation, an appropriate FiO₂ must be used.
In pregnant women, the nitrous oxide concentration must not exceed 50% v/v in the oxygen mixture due to the inherent toxicity of the drug.
The induction time is 2–5 minutes with a nitrous oxide concentration of 70–75% v/v.
After induction, nitrous oxide is typically used at concentrations between 50% and 70% v/v, supplemented with oxygen. The nitrous oxide percentage may be reduced according to clinical parameters and the anaesthetic plan.
Nitrous oxide at the maximum permitted concentration cannot induce anaesthesia alone and is therefore used in combination with other anaesthetics administered intravenously or by inhalation.
Information on dosing of nitrous oxide and additional inhaled anaesthetics for maintenance of anaesthesia is generally available in the product leaflets of those agents. When combined with intravenous anaesthetics, the intravenous dose should be adjusted accordingly.
In general, the effects of nitrous oxide, if used as the sole active agent, do not depend on the patient's age.
Nitrous oxide should not be administered for more than 12 consecutive hours due to its myelotoxicity. Continuous exposure (>24 hours) increases the risk of bone marrow depression.
As an analgesic
Nitrous oxide used as a single analgesic/anaesthetic/sedative (always combined with oxygen) at concentrations below 50% v/v relieves pain, provides sedation, and reduces agitation, and normally does not affect the level of consciousness or the ability to carry on a conversation. At these concentrations, respiration and reflexes remain unchanged.
The pain-relieving and sedative effects are dose-dependent, as are the effects on cognitive functions.
Patient exposure to nitrous oxide as an analgesic should not exceed 1 hour and should not be repeated for more than 15 consecutive days.
Method of Administration
Nitrous oxide must always be administered under the supervision of medical personnel, who determine whether the medicinal product can be administered and at what dose, in an appropriate setting equipped for emergency cardiorespiratory resuscitation.
Instructions from medical personnel must be strictly followed when administering the gas.
Personnel using nitrous oxide must be adequately trained and updated on its use, which must be administered with appropriate equipment in well-ventilated rooms ensuring immediate air exchange, with ventilation systems preventing excessive gas concentrations in ambient air, and using, for example, so-called "double masks" (active nasal masks), particularly recommended for dental procedures.
In ambulances, the delivery device may be connected to an extraction system or a double mask may be used.
Air quality must be monitored according to local regulations, and occupational exposure to nitrous oxide must remain below the hygienic limits established by professional guidelines and health and safety legislation, especially for pregnant personnel.
Nitrous oxide is normally administered via an orotracheal or nasotracheal tube in the operating room, and via a tight-fitting facial or nasal mask in other settings. The patient may breathe spontaneously or with ventilatory support (assisted or mechanical ventilation).
Nitrous oxide must be administered in combination with oxygen, using equipment that ensures delivery of a non-hypoxic mixture of nitrous oxide and oxygen. Such equipment must include oxygen concentration monitoring and a safety system preventing the administration of a hypoxic mixture (FiO₂ <21% v/v).
Due to the risk of loss of consciousness and coma, when nitrous oxide is used outside the operating room, analgesic administration is acceptable only in a mixture containing 50% v/v oxygen. The device used must make it impossible to administer mixtures with nitrous oxide concentrations exceeding 50% v/v.
Throughout the period of nitrous oxide use, both the patient and the method of administration must be monitored to ensure safe inhalation of the gas.
The patient must be monitored by medical personnel until the end of administration and until full recovery of consciousness.
Cylinders and fixed cryogenic containers are intended exclusively for containing/transporting nitrous oxide for inhalation, for therapeutic use.
NOTE: FOR FURTHER DETAILS, CONSULT THE INSTRUCTIONS FOR USE OF THE CONTAINER
Storage

Read the container instruction and user manual carefully.
Check that all equipment is in good condition.
Store outdoors or in well-ventilated areas, in fenced and rain-protected zones, shielded from direct sunlight and away from heat sources (locked spaces reserved for medicinal gases).
Do not expose to heat sources or high temperatures (above 50°C).
Protect from electrical lines and ensure proper grounding.
Keep away from flammable material storage and combustible materials in general (contact with combustible materials may cause fire).
Do not smoke or use open flames near the product.
Keep the container (cylinder) clean and dry, avoiding any contact with grease or oils (do not lubricate valves or fittings).
Ensure containers are undamaged and avoid impacts and gas leakage.
Close valves to block gas release when not in use.
Keep cylinders and cylinder packs upright, with valves closed, protective caps and heat-shrink sleeves in place, and properly secured to prevent accidental impacts or falls.
Do not use damaged packages.
Empty and full containers must be stored separately.
Containers containing other types of gases must be stored separately.
Excessive storage of full containers should be avoided.
In case of fire risk, move to a safe area after closing valves.
In case of leakage, close the cylinder valve immediately if safe to do so. If the valve cannot be closed, move the container to a safe outdoor location to allow gas to escape.
Vapours may cause drowsiness and dizziness.

Transport of Cylinders
Cylinders must be transported using appropriate means (e.g. trolley equipped with chains, barriers, or rings) to protect them from impact, falling, and gas leakage. Cylinder handling must always be performed with the protective cap in place. During vehicle transport, cylinders must be securely fastened, preferably in an upright position. Permanent vehicle ventilation must be ensured, and smoking is prohibited.
During Gas Use

Cylinders and fixed containers must not be used if visibly damaged, suspected of damage, or exposed to extreme temperatures.
Before opening the cylinder valve, place the cylinder upright and maintain this position during administration.
Open and close container closure systems gradually and carefully (do not use pliers or other tools to open or close the cylinder valve) to prevent damage.
Do not force valves during opening or closing. Do not alter the container shape.
Never stand directly in front of the gas outlet; always position yourself to the side. Do not expose yourself or the patient to direct gas flow.
Nitrous oxide administration must be performed at appropriate pressure, with controlled flow rate between container and patient.
Do not use oil or grease in contact with the gas.
Handle equipment with clean hands, free from grease or oil traces.
Do not completely empty the container.
After use, close the cylinder valve.
In case of gas leakage, close the valve and contact the technical support service of the supplier indicated in the container's user manual.
Use only containers suitable for the product and intended operating temperatures.
Use specific and compatible connectors, connecting tubes, or hoses compatible with nitrous oxide.
It is strictly forbidden to modify connectors, delivery equipment, or their accessories or components in any way (OIL AND GREASE MAY SPONTANEOUSLY IGNITE ON CONTACT WITH NITROUS OXIDE).
Do not lubricate or attempt to repair defective valves.
It is strictly forbidden to handle equipment or components with hands, clothing, or face contaminated with grease, oil, creams, or ointments.
Do not use greasy creams or lipsticks.
Do not smoke.
Do not bring open flames near the container.
No electrical equipment capable of producing sparks should be used near patients receiving oxygen.
Do not use oils or greases on connectors, valves, or any material in contact with the gas.
Never introduce nitrous oxide into any device that may contain combustible materials, particularly greasy substances.

Disposal

Store empty cylinders with valves closed.
Do not discharge into sewers, basements, or pits where gas accumulation may be hazardous. Discharging pressurized gas is not permitted.
Return empty or unused containers, even if only partially empty, to the supplier. Any residual medicinal product in the cylinder will be safely eliminated through appropriate procedures in a well-ventilated area by the company responsible for subsequent refilling of the container.
Unused medicinal product and waste derived from this medicinal product must be disposed of in accordance with current local regulations.

Nitrous oxide Sapio Life

Package leaflet: Information for the patient